Personalized Antidepressant Selection and Pathway to Novel Treatments: Clinical Utility of Targeting Inflammation

Manish K Jha, Madhukar H Trivedi, Manish K Jha, Madhukar H Trivedi

Abstract

Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP)-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments.

Keywords: antidepressants; blood-brain barrier; c-reactive protein; depression; experimental drugs; inflammation; monoamines; monoclonal antibodies.

Conflict of interest statement

Jha received contract research support from Acadia Pharmaceuticals. Trivedi is or has been an advisor/consultant and received fees from Alkermes, AstraZeneca, Cerecor, Eli Lilly & Company, Lundbeck, Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Pfizer Inc., SHIRE Development and Takeda. In addition, he has received grants/research support from the National Institute of Mental Health and National Institute on Drug Abuse.

Figures

Figure 1
Figure 1
Superiority of CRP-matched treatment assignment to SSRI monotherapy of combination of bupropion and SSRI. CRP is c-reactive protein, CO-MED is Combining Medications to Enhance Depression Outcomes, SSRI is selective serotonin reuptake inhibitor. This figure is based on the findings reported by Jha et al. [92]. CRP-matched treatment assignment refers to participants who received escitalopram only and had CRP

Figure 2

Theoretical framework for developing novel…

Figure 2

Theoretical framework for developing novel antidepressants by targeting inflammatory pathways. Two distinct pharmacologic…

Figure 2
Theoretical framework for developing novel antidepressants by targeting inflammatory pathways. Two distinct pharmacologic interventions with the potential to reduce depressive symptom severity. In the first pathway, activation of indoleamine oxygenase (IDO) results in increased levels of kynurenine, which is taken up by LAT-1 transporters and converted to Quinolinic acid by microglial cells. This results in glutamatergic excitotoxicity and depressive symptoms. Blockade of the LAT-1 transporter by a pharmacologic agent can disrupt this cascade and reduce depressive symptoms and mitigate central nervous system (CNS) effects of peripheral inflammation. Similarly, anti-cytokine treatments may be effective in depressed patients with elevated levels of inflammatory cytokines (interleukin 6 or IL-6, interleukin 17 or IL-17, and tumor necrosis factor alpha or TNF-α), which result in blood-brain barrier (BBB) dysfunction.
Figure 2
Figure 2
Theoretical framework for developing novel antidepressants by targeting inflammatory pathways. Two distinct pharmacologic interventions with the potential to reduce depressive symptom severity. In the first pathway, activation of indoleamine oxygenase (IDO) results in increased levels of kynurenine, which is taken up by LAT-1 transporters and converted to Quinolinic acid by microglial cells. This results in glutamatergic excitotoxicity and depressive symptoms. Blockade of the LAT-1 transporter by a pharmacologic agent can disrupt this cascade and reduce depressive symptoms and mitigate central nervous system (CNS) effects of peripheral inflammation. Similarly, anti-cytokine treatments may be effective in depressed patients with elevated levels of inflammatory cytokines (interleukin 6 or IL-6, interleukin 17 or IL-17, and tumor necrosis factor alpha or TNF-α), which result in blood-brain barrier (BBB) dysfunction.

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